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Negr1 controls adult hippocampal neurogenesis and affective behaviors

Molecular Psychiatry volume 24, pages 1189–1205 (2019)Cite this article

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Abstract

Recent genome-wide association studies on major depressive disorder have implicated neuronal growth regulator 1 (Negr1), a GPI-anchored cell adhesion molecule in the immunoglobulin LON family. Although Negr1 has been shown to regulate neurite outgrowth and synapse formation, the mechanism through which this protein affects mood disorders is still largely unknown. In this research, we characterized Negr1-deficient (negr1−/−) mice to elucidate the function of Negr1 in anxiety and depression. We found that anxiety- and depression-like behaviors increased in negr1−/− mice compared with wild-type mice. In addition, negr1−/− mice had decreased adult hippocampal neurogenesis compared to wild-type mice. Concurrently, both LTP and mEPSC in the dentate gyrus (DG) region were severely compromised in negr1−/− mice. In our effort to elucidate the underlying molecular mechanisms, we found that lipocalin-2 (Lcn2) expression was decreased in the hippocampus of negr1−/− mice compared to wild-type mice. Heterologous Lcn2 expression in the hippocampal DG of negr1−/− mice rescued anxiety- and depression-like behaviors and restored neurogenesis and mEPSC frequency to their normal levels in these mice. Furthermore, we discovered that Negr1 interacts with leukemia inhibitory factor receptor (LIFR) and modulates LIF-induced Lcn2 expression. Taken together, our data uncovered a novel mechanism of mood regulation by Negr1 involving an interaction between Negr1 and LIFR along with Lcn2 expression.

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Acknowledgements

The work was supported by the National Research Foundation of Korea, funded by the Ministry of Science and ICT (NRF-2013R1A2A2A01067248, NRF-2016M3C7A1905074, and NRF-2016M3C7A1905481), Republic of Korea.

Author contributions

KN, HL, TYC, SL, SYC, and SJL designed the research study. KN, SJK, and JYK performed all behavioral tests and analysis. KN and HL performed the Golgi stain, cell culture experiments, and the real-time RT-PCR. KN performed the immunohistochemistry, plasma corticosterone assay, and virus experiments. HL and YJ performed the western blot assays, and HL performed the immunoprecipitation assays. KN and TYC performed the electrophysiology experiments. HK performed the yeast two-hybrid screening and GST pulldown assay. KN, SL, SYC, and SJL wrote the manuscript, and all authors commented on the manuscript. SJ, SYC, and SJL supervised the project.

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  1. These authors contributed equally: Kyungchul Noh, Hyunkyoung Lee, Tae-Yong Choi

Authors and Affiliations

  1. Department of Physiology and Neuroscience, Dental Research Institute, Seoul National University School of Dentistry, Seoul, Republic of Korea

    Kyungchul Noh, Hyunkyoung Lee, Tae-Yong Choi, Soo-Joeng Kim, Se-Young Choi & Sung Joong Lee

  2. Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon, Republic of Korea

    Yeonhee Joo, Hyejin Kim & Soojin Lee

  3. Department of Oral and Maxillofacial Surgery, Dental Research Institute, Seoul National University School of Dentistry, Seoul, Republic of Korea

    Jin Young Kim & Jeong Won Jahng

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Noh, K., Lee, H., Choi, TY. et al. Negr1 controls adult hippocampal neurogenesis and affective behaviors. Mol Psychiatry 24, 1189–1205 (2019). https://doi.org/10.1038/s41380-018-0347-3

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